Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-:36])C.[K+].O=O.C(O)(=O)C>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][C:22]2[C:21](=[O:36])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(OCc1ccccc1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
2-benzyloxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.63 g, 8.51 mmol) ) (prepared as in Example 10) was dissolved in dry DMF (25 mL). Potassium t-butoxide (2.40 g, 21.4 mmol) was introduced in one portion and the suspension was stirred until a clear solution was obtained. Oxygen gas was then passed through the solution via a syringe needle for 16 h. The reaction was quenched by the addition of glacial acetic acid (1.23 mL, 21.0 mmol) and poured into water (250 mL), which resulted in a precipitate that was collected by filtration. The product was purified by flash chromatography (2-10% MeOH/CHCl3) to yield the product as a red powder.
Reaction SMILES: [N:1]1([N:7]([CH3:31])[C:8]([C:10]2[C:14](O)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-:32].[F-].[F-].C(N(SN(CC)CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1([N:7]([CH3:31])[C:8]([C:10]2[C:14]([F:32])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [F-]
Reactant: CN(C(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1O)N1CCCCC1
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1F)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 600 mg of the compound of EXAMPLE 1 in 24 ml of DCM is added dropwise to a solution of 0.19 ml of diethylamino sulfide trifluoride in 24 ml of DCM at -78° C. under nitrogen. The mixture is allowed to warm up slowly to 0° C. and then stirred for one hour at 0° C. The reaction mixture is poured into saturated NaHCO3 solution and then extracted with DCM, washed with saturated NaCl solution and dried over MgSO4. The residue is chromatographed on fine silica using AcOEt/toluene (5/95 to 40/60; v/v) as the eluent to give 250 mg of the expected product, m.p.=184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:12])([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([C:20]3=O)[CH2:18]1)[CH2:24]2)=[O:16].C(O)(=O)C.[BH4-].[Na+]>C(O)C.O>[CH3:13][O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH:20]3[NH:10][CH2:9][C:8]([NH2:12])([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH3:11])[CH2:18]1)[CH2:24]2)=[O:16]
Reactant: CC(N)(CN)c1cccc(Cl)c1
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Temperature: 0 °C
Reaction time: 17 h
Yield: 86.5 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-propane-1,2-diamine (3.4 g) and 4-oxo-adamantane-1-carboxylic acid methyl ester (CAS 56674-88-5, 3.85 g) in ethanol (50 mL) was added acetic acid (0.7 mL) and reaction mixture was refluxed for 4 h, after which it was cooled to 0° C. and NaBH4 was added. The reaction mixture was then slowly brought to room temperature and left at stirring for 17 h. The reaction was monitored by TLC. After completion, water (30 mL) was slowly added. The reaction mixture was concentrated at reduced pressure to remove the ethanol. The aqueous layer was extracted with DCM (3×50 mL) and the organic layers were then dried over Na2SO4 and then concentrated to get crude desired 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (6 g) as a mixture of E/Z isomers. The compound was used in the next step without further purification. MS (ESI): 377.4 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:15][CH3:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([I:28])[CH3:27]>>[I-:28].[C:1]1([NH:7][C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)([CH2:26][CH3:27])[CH2:15][CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CCCNC(=O)Nc1ccccc1)CCc1ccc(Cl)cc1
Reactant: CCI
Product: CC[N+](CC)(CCCNC(=O)Nc1ccccc1)CCc1ccc(Cl)cc1
Product: [I-]
Yield: 78 %

Procedure:
A solution of N-phenylcarbamoyl-N′-[2-(4-chlorophenyl)ethyl]-N′-ethyl-1,3-diaminopropane (Compound 1, 13.7 mg, 0.0381 mmol) in ethyl iodide (2 ml) was refluxed for 3 h, and concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and the plate was developed with 17% methanol/chloroform to afford [3-(phenylureido)propyl][2-(4-chlorophenyl)ethyl]diethylammonium iodide (15.4 mg, 78%): MS(ES+) m/e 388 [M-I]+; 1H NMR (400 MHz, CDCl3) δ 8.15 (br, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.16 (m, 6H), 6.90 (m, 1H), 6.54 (m, 1H), 3.50 (m, 2H), 3.33 (m, 6H), 3.25 (m, 2H), 2.96 (m, 2H), 1.91 (m, 2H), 1.28 (t, J=7.1 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[C:7](=O)[C:6]=2[CH:19]=1.C>O1CCOCC1.C(O)C.S(=O)(=O)(O)O.C(Cl)Cl.[Pd]>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[CH2:7][C:6]=2[CH:19]=1
Reactant: Cc1cccc(-c2coc3cc(O)c(O)cc3c2=O)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cccc(C2COc3cc(O)c(O)cc3C2)c1

Procedure:
6,7-Dihydroxy-3-(3-methylphenyl)-4H-1-benzopyran-4-one (1.2 g), dissolved in a mixture of dioxan/ethanol 4:6 (40 ml), is hydrogenated for 24 h at room temperature over palladium 5% on active charcoal (0.48 g) in the presence of a few drops of concentrated sulphuric acid. After filtration of the catalyst, the filtrate is evaporated to dryness under vacuum. An oil is obtained which is dissolved in methylene chloride. The solution is washed with water and dried over magnesium sulphate to give an oil which on crystallization yields 3,4-dihydro-6,7-dihydroxy-3-(3-methylphenyl)-2H-1-benzopyran, m.p. 146°-148°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reaction time: 6 h
Yield: 77.5 %

Procedure:
To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) dissolved in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred for 6 h, water was added, and the mixture was extracted with dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate then dried over MgSO4. The dried organic layer was evaporated to give 11.00 g (78%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR(CDCl3) δ4.32 (s, 2H), 5.88 (tt, 1H), 6.08 (t, 1H), 6.17-6.22 (m, 2H), 7.00 (t, 1H), 7.11 (dd, 1H), 7.24-7.27 (m, 2H), 7.33 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[OH:16].CO.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[C:7]2[OH:16]
Reactant: COC(=O)c1cc(O)c2ccc(OC)c(Cl)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate 214 (36.5 g, 0.145 mol) in a mixture of 1:1 of MeOH:THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H20 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCl. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6%) of compound 215 as a white solid. EI MS (m/z) 253.9 [M+H].
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>ClCCl>[CH2:15]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[CH:8]([F:10])[F:9])[CH3:16]
Reactant: CCO
Reactant: NC(CCC(=O)O)C(F)F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCC(N)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 15 ml of dichloromethane is treated with 2 mmole of thionyl chloride at 25° C. for one hour after which 20 ml of ethanol is added. The solution is stirred at 25° C. for one hour, washed with water, dried and concentrated to afford 4-amino-4-difluoromethylbutyric acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([OH:13])[CH:8]=[N:7][C:6]=2[N:5]([C@@H:14]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]2[OH:16])[CH:4]=1)#[N:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([OH:13])[CH:8]=[N:7][C:6]=2[N:5]([C@@H:14]2[O:20][C@H:19]([CH2:21][O:22][C:17](=[O:18])[CH3:19])[C@@H:17]([O:18][C:15](=[O:16])[CH3:14])[C@H:15]2[O:16][C:10](=[O:12])[CH3:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncn(O)c(=O)c12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C#N)c3c(=O)n(O)cnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 5 h

Procedure:
5-Cyano-3-N-hydroxy-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidin-4-one was dissolved in a mixture of 50 ml of pyridine and 25 ml of acetic anhydride. The solution was allowed to stand at room temperature for 5 hr and evaporated in vacuo to a thick oil. This residue was triturated with 100 ml of ethanol and the mixture was evaporated in vacuo to a solid foam which was again triturated with 100 ml of ethanol and evaporated in vacuo to dryness. The resulting foam was heated at reflux temperature with 100 ml of methanol for 1 hr. The methanol was removed in vacuo and an additional 100 ml of methanol was added and removed in vacuo to furnish a solid foam which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:26][C:27]([O:29][CH:30]1[CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH:32]([CH3:39])[CH2:31]1)=[O:28]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([C:15]#[N:16])([CH2:26][C:27]([O:29][CH:30]1[CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH:32]([CH3:39])[CH2:31]1)=[O:28])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C#N)NC(=O)OC(C)(C)C
Reactant: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)(CC(=O)OC1CC(C)CCC1C(C)C)NC(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Ethyl 2-(tert-butoxycarbonylamino)-2-cyanoacetate (1.20 g, 526 mmol) prepared in the same manner as Reference Example 1, acetone (2.3 ml), powdered potassium carbonate (872 mg, 6.31 mmol) and potassium iodide (175 mg, 1.05 mmol) were mixed, a solution of menthyl chloroacetate (1.22 g, 5.26 mmol) dissolved in acetone (1.1 ml) was added dropwise thereto at 10-20° C., and the mixture was stirred at the same temperature overnight. Insoluble materials were removed by filtration, the filtrate was concentrated in vacuo and toluene was added to the residue. The organic layer was washed with water and concentrated in vacuo to give ethyl 2-(tert-butoxycarbonylamino)-2-cyano-3-[(−)menthyloxycarbonyl]propionate (1.10 g, yield 49.3%) as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7](N1CCC(=O)C1)[CH3:8].[N+:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:17])=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:7]([O:5][C:1]([C:2]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:15][O:17][C:3]=1[CH3:4])=[O:6])[CH3:8]
Reactant: O=[N+]([O-])CCCc1ccccc1
Reactant: C/C=C/C(=O)O
Reactant: CCN1CCC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CCc2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 48.5 g. (0.265 mole) ethyl-3-pyrrolidone crotonate 48.2 g. (0.291 mole) 1-nitro-3-phenylpropane and 208 ml. (1.490 mole) triethylamine in 500 ml. chloroform is cooled to 0° and treated by the dropwise addition of 44.6 g. (0.291 mole) phosphorous oxychloride in 105 ml. chloroform. The addition takes approximately three hours and the temperature is maintained at about 0°±5°. After the addition the mixture is stirred at room temperature over night. The resulting mixture is then washed once with cold water, three times with 6 N hydrochloric acid, once with 1 N sodium hydroxide and once with saturated sodium chloride. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled and the fraction collected at about 145°-150°/0.45 mm to give 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester. Identified by NMR and IR.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C.O>[CH:20]1([CH2:23][N:5]2[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:22][CH2:21]1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(CC2CC2)c(C(N)=O)c1[N+](=O)[O-]

Procedure:
A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO98/49166) (40.0 g, 217 mmol) in dry DMF (300 ml) was treated with cesium carbonate (77.8 g, 239 mmol). To this, in a single portion, was added cyclopropylmethyl bromide (22.9 ml, 239 mmol) and the resultant suspension stirred at RT for 6 h. After condensation in vacuo, the residue was partioned between ethyl acetate (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partioned between water (200 ml) and methylene chloride (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried over MgSO4, and condensed to a solid (40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, methylene chloride:methanol 98:2) crystallising from a mixture of methylene chloride (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (12 g, 50 mmol). Crystallisation of the mother liquors from acetonitrile gave the more polar component (Rf=0.19, methylene chloride:methanol 98:2) (10 g, 42 mmol) which was confirmed as the 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe experiements. The mother liquors contained further material as a mixture of regioisomers (20 g, 84 mmol).